Methods, pharmaceutical and therapeutic compositions for administering adenosine

ABSTRACT

The invention discloses methods for the chronic administration of adenosine, which contrary to the acute delivery of the drug by injection or infusion, acts in desensitizing adenosine receptors towards the action of adenosine. The methods and oral compositions of adenosine triphosphate (ATP), which is degraded to adenosine in vivo, can be used in the treatment of disorders and diseases that are therapeutically targeted by agonists or antagonists of adenosine receptors. One example is the stimulation of lipolysis in achieving weight loss in humans and in the treatment of obesity.

FIELD OF THE INVENTION

[0001] The invention relates to the chronic elevation of endogenousadenosine levels by the use of stable adenosine 5′-triphosphate (ATP)compositions, which are taken orally over a period of time. The elevatedlevels of adenosine, produced by the in vivo degradation of ATP, act indecreasing the sensitivity (desensitization) of adenosine receptors. Thedecrease in sensitivity can materialize through a decrease in numbers ofreceptors (density) or through a reduction in the receptor's couplingactivity (intracellular signal transduction). The reduced sensitivity ofcertain adenosine receptors towards their natural agonist—adenosine, canbe useful by itself or in combination with adenosine antagonists, whichare much more active towards desensitized adenosine receptors. Examplesfor utilization of these methods are in the treatment of disorders ordiseases, which are controlled by biochemical mechanisms regulated byadenosine receptors. One such case is in the treatment of obesity, whichcan be treated by the metabolic stimulation of weight loss. Lipolysis,the degradation of fat (triglycerides) in adipose tissue to free fattyacids and glycerol, is known to be inhibited by the interaction ofadenosine with A₁ adenosine receptors of the adipocyte (fat cell). Theinteraction of adenosine with adipose tissue A₁ adenosine receptors wasshown to stimulate lipogenesis—the buildup of triglycerides (fat) in fatcells. Methods for desensitization of A₁ adenosine receptors in a humanin vivo, thus significantly diminishing the activity of endogenousadenosine, are disclosed and taught and are utilized for the effectivereduction of weight in humans. Effective weigh loss in humans can beachieved either by the desensitization of the adipose tissue adenosineA₁ receptors by themselves, or by desensitization in combination withadenosine antagonists such as caffeine or theopliyllinc, which are muchmore effective in blocking the action of adenosine once its receptorsbecame desensitized. The use of chronic administration of adenosine forthe purpose of desensitization of adipose tissue A₁ adenosine receptorsin the induction of weight loss in humans, demonstrates the utility ofthe present invention. Obesity is the costliest disease inindustrialized countries. It is associated with a variety of chroniclife-threatening diseases such as type II diabetes, hypertension,stroke, and heart disease. The definition of obesity is an excessiveaccumulation of fat in the body. Obesity in terms of a disease isdefined if body weight is 20% or more above the desirable weight(Council on Scientific Affairs, J. Amer. Med. Assoc. 1988). Overweightis defined if body weight exceeds the desirable weight by less than 20%.Desirable weight in humans has been well-defined (council on scientificaffairs, JAMA 1988). Weight loss in overweight or obese humans can beachieved by diet, physical activity and behavior modification or bytreatment with drugs. There are three main ways for the pharmaceuticaltreatment of overweight or obesity: 1. Inhibition of absorption ofnutrients in the intestine; 2. Modulation of the activities of themetabolic and central nervous system (hypothalamic) satiety and foodconsumption (hunger) signals; and 3. Induction of energy dissipation intissues, especially adipose tissue (thermogenesis). The methodsdisclosed here of the chronic administration of adenosine by the oraldelivery of the pro-drug ATP, deal with the induction of energydissipation, in the form of degradation of fats in adipose tissue.

BACKGROUND OF INVENTION

[0002] The physiological activities of adenosine triphosphate andadenosine were first discovered in 1929 (for a review, see Williams andBurnstock 1997). It is now known that adenosine exerts its physiologicaleffects by interacting with specific receptors, several subtypes ofwhich (A₁, A_(2A), A_(2B) and A₃) have been characterized and shown toregulate specific physiological processes. Adenosine triphosphate inturn, exerts its physiological activities by interacting with anotherfamily of receptors termed P₂ receptors (Burnstock 1990). The A₁adenosine receptors were shown to regulate significant brain (Williamsand Burnstock 1997), heart and adipose tissue functions (van der Graafet al. 1999) by their in vivo interactions with endogenous,extracellular adenosine in animals and humans. The function of these A₁adenosine receptors is to transmit regulatory signals from adenosine,which is the product of extracellular metabolism, to the inside of thecells. This signal transduction is in turn achieved by a family of Gproteins-linked to cell membrane A₁ adenosine receptors (Linden 1991).The G_(i) protein, which interacts with the A₁ adenosine receptors, actsin inhibiting the intracellular activity of adenyl cyclase, the enzymecatalyzing the synthesis of cyclic AMP (cAMP) inside the cell. Thus,upon interaction of extracellular adenosine with A₁ adenosine receptors,the G_(i) proteins coupled to this receptor inhibit the synthesis ofcAMP, resulting in lower cellular levels of cAMP and in the case ofadipose A₁ adenosine receptors, overall inhibition of lipolysis (LaNoueand Martin 1994). Because signaling from the adipose tissue A₁ adenosinereceptors inhibit the degradation of triglycerides to free fatty acidsand glycerol (lipolysis), the possibility of excessive activity of theadipose tissue A₁ adenosine receptors was considered as a genetic factorin obesity. This indeed turned out to be the case in genetically obesemice and rats as well as in humans. In these cases the adipose tissue A₁adenosine receptors were found to be extremely active in transmittingtheir signal to the G_(i) proteins with little dependence on thepresence of extracellular adenosine (LaNoue and Martin 1994).

[0003] Therefore, the inhibition of the activity of adipose tissue A₁adenosine receptors via antagonism of adenosine or a mediated reductionof the efficacy of the receptors' coupling to G_(i) proteins wouldconstitute a reasonable approach to weight control or obesity in humans.Methods utilizing the administration of A₁ adenosine receptorantagonists, such as caffeine (1,3,7-trimethylxanthine), theophylline(1,3-dimethylxanthine) or synthetic A₁ adenosine receptor antagonists,did not produce weight loss in genetically obese experimental animals(Xu et al. 1998). However, Caffeine, which is an establishednon-specific A₁ adenosine receptor antagonist (Jacobson and van Rhee1997), was shown effective in inducing weight loss in humans as part ofa variety of regimens discussed in several issued U.S. patents.

[0004] U.S. Pat. No. 5,422,352 discloses a combination of caffeine andephedrine in a ratio of about 12:1 as a composition for reducing weightin humans. U.S. Pat. No. 5,480,657 discloses a composition of caffeine,chromium and fructose for the treatment of obesity. U.S. Pat. No.5,679,358 discloses compositions containing caffeine, theophylline ortheir derivatives along with other ingredients for the purpose ofreduction of superfluous fat of any origin by topical application. Forexample, this patent refers to caffeine, theophylline or pentoxifyllineas lipolytic agents, though no mechanism is discussed in thespecifications. U.S. Pat. No. 5,798,101 discloses compositions andmethods for reducing weight consisting of St. John's Wart herbalextracts with or without caffeine. Caffeine and theophilline have beenestablished as non-specific antagonists of adenosine receptors, namely,they interact with both A₁ and A_(2A) adenosine receptors with moderateaffinity (Jacobson and van Rhee 1997). All of the issued U.S. patentsdiscussed above refer to caffeine as a “stimulator of metabolism” or inone case a “lipolytic agent”.

[0005] A published placebo-controlled double blind human clinical studyhas demonstrated that caffeine ingestion increased the levels of freefatty acids (the products or lipolysis) in young men in a statisticallysignificant manner. The increase in free fatty acids after caffeinechallenge was not related to alterations in norepinephrine kinetics orfat oxidation (Arciero et al. 1995).

[0006] Several physiological sites are regulated to a significant degreeby A₁ adenosine receptors. These are the brain (Williams and Burnstock1997), the heart (Kollias-Baker et al. 1995), adipose tissue (van derGraaf et al. 1999) and the coordination of glucose and lipid metabolism(van Schaick et al. 1998). Attempts to affect the function of specificorgans or tissues by the use of adenosine or synthetic adenosineanalogues acting as agonists or antagonists would seemingly produceglobal effects leading to intolerable side effects. This is not the casehowever, because of the blood brain barrier, which protects the brainfrom hydrophilic agents and the much greater sensitivity ofadipocytes-metabolic A₁ adenosine receptors towards adenosine and itsagonists in comparison to the heart A₁ adenosine receptors. The overallsensitivity of adipose tissue anti-lipolytic A₁ adenosine receptorstowards adenosine, considering both the tissue density of the receptorsand the sensitivity of the receptors' intracellular coupling, wasreported to be 38 times higher than the sensitivity of A₁ adenosinereceptors regulating cardiac functions (van der Graaf et al. 1999).Adipose tissue-metabolic A₁ adenosine receptors are therefore a goodtherapeutic target, taking into account their sensitivity towardsadenosine in comparison to other potential therapeutic targets, which isexpected to yield significant efficacy with a manageable spectrum ofside effects. One condition is that the agonist for the adiposetissue-metabolic A₁ adenosine receptors has to be a relatively lowaffinity agonist, since a high affinity agonist is expected to interactwith low affinity A₁ adenosine receptors on other organs and producesignificant side effects (van der Graaf et al. 1999). Adenosine itselfis known to be such an agonist (Jacobson and van Rhee 1997). The reasonthat it has not been used for these therapeutic targets is its extremelyshort blood plasma half-life, limiting any efficacy and potentialusefulness (Williams and Burnstock 1997). The present inventiondiscloses and teaches a method for consistently and chronicallyelevating blood plasma adenosine levels for achieving adiposetissue-metabolic therapeutic targets without any side-effects.

[0007] The short blood plasma half-life of adenosine of 3-6 seconds(Williams and Burnstock 1997) made it an ideal compound for thetreatment of supraventricular tachycardia, a form of cardiac arrhythmia,for which use it has been approved in man as a bolus injection(Kollias-Baker et al. 1995). The therapeutic use of adenosine in theform of a bolus injection has been successful strictly because of theacute nature of the adenosine administration, preventing what is definedas receptor desensitization (Linden 1997). Chronic administration ofsynthetic A₁ adenosine receptor agonists was reported to produce markeddesensitization of the heart's adenosine A₁ receptors (Shryock et al.1989; Lee et al. 1993)

[0008] Desensitization of receptors is a general phenomenon, wherebychronic exposure of sensitive receptors to their agonists can produce amarked reduction in the capacity of the receptors to respond to the sameor related agonists. The same phenomena have also been termedrefractoriness, tolerance or tachyphylaxis (Hoppe and Lohse 1995). TheA₁ adenosine receptors, both in cardiac and adipose tissues have beendemonstrated to undergo desensitization after chronic exposure toadenosine analogues that are proven agonists for the A₁ adenosinereceptors. Desensitization of the A₁ adenosine receptors in both tissueswas demonstrated to be mediated by both a reduction in receptor density(numbers) and a decrease in the sensitivity of the receptor's couplingto the intracellular G_(i) proteins (Hoppe and Lohse 1995). The G_(i)proteins act in transducing the receptors' signal inside the targetcell. The A₁ adenosine receptors desensitization is used as atherapeutic target as disclosed and taught by the present invention. Byreducing the overall sensitivity of the adipose tissue-metabolic A₁adenosine receptors as a result of chronic administration of adenosine,the effectiveness of adenosine as an endogenous anti-lipolytic agent issignificantly diminished. As importantly, antagonism of adenosine atthese sites, by common A₁ adenosine receptor antagonists such ascaffeine or theophylline, is markedly enhanced. Desensitization ofadipose tissue-metabolic A₁ adenosine receptors does not affect heart orbrain A₁ adenosine receptors because of the heart's receptors much lowersensitivity (van der Graaf 1999) and the brain's effective barrieragainst systemic adenosine (Williams and Burnstock 1997).

SUMMARY OF THE INVENTION

[0009] The present invention discloses and teaches:

[0010] The preparation of a stable pharmaceutical and therapeuticcomposition of adenosine 5′-triphosphate (ATP) or physiologicallyacceptable salt thereof suitable for oral delivery. The inventionprovides for a stable oral dosage form such as a pill of ATP orphysiologically acceptable salt thereof along with fillers, binders,stabilizers and enteric coating materials. The objective of the oraldelivery of ATP is to achieve systemic absorption of adenosine.

[0011] A method for the chronic administration of adenosine using an ATPoral dosage form (e.g. pill) as a pro-drug for the chronic elevation ofextracellular adenosine. Extracellular adenosine interacts with avariety of adenosine receptors regulating functions of organs andtissues.

[0012] A method for the chronic administration of adenosine for thepurpose of desensitizing adipose tissue-metabolic A₁ adenosinereceptors. The utility of this method is in decreasing the sensitivitiesof these receptors towards adenosine and at the same time increasing thesensitivities of these receptors towards adenosine antagonists such ascaffeine or theophilline. This method is used for the purpose ofinducing weight loss in humans or in the treatment of obesity in humans.Since the adipose tissue-metabolic A₁ adenosine receptors act ininhibiting lipolysis (degradation of fats), reductions in theiractivities as a result of chronic exposure to adenosine is suffecient toinduce lipolysis and effective weight loss. Chronic exposure toadenosine, can be supplemented by caffeine or theophilline, bothcommonly used drugs in order to further reduce the activities of adiposetissue-metabolic A1 adenosine receptors, thus achieving a more enhancedweight loss. The term “chronic administration” and similar terms usedherein refer to prolonged or substantially sustained release over anextended period of time, typically at least about 96 hours.

DETAILED DESCRIPTION OF THE INVENTION

[0013] Pharmacologically active substances, such as ATP, which undergorapid degradation inside parts of the gastrointestinal tract or insidethe vascular bed, are coated with an enteric polymer that dissolves at aspecific pH. In the case of ATP, the catabolic enzymes that catalyze thedegradation of purines are present in the stomach and the proximal smallintestines (Mohamedali et al. 1993). Thus a pH-sensitive enteric coatingcan be designed to release ATP as the therapeutically active agent inthe distal part of the small intestine, the ileum, where catabolicactivities that catalyze the degradation of ATP are minimal (Mohamedi etal. 1993). The human stomach has a variable acidic pH of about 1 to 2and the transit time of a pill through the stomach is between 20 minutesand 2 hours, depending on the prandial state. An ATP pill passingthrough the stomach intact would enter the small intestine, whichconsists of the duodenum, jejunum and ileum. Transit time of a pillthroughout the small intestine is relatively steady at approximately 3hours. Following the small intestine, an enteric stable pill then passesthrough the large intestine, which consists of the caceum, the ascendingcolon, the transverse colon, the descending colon and the sigmoid colon.Total transit time through the large intestine is about 30-35 hours.Even though the distal part of the small intestine, the ileum, hassomewhat greater catabolic activities on ATP than the colon, three ofits properties make areas of the ileum very suitable sites for therelease of ATP from enteric pills. First, a pH spectrum that enables thedesign of a pH-sensitive enteric coated pill, releasing the ATP at thedesired site. The pH of the small intestine gradually rises from about5-5.5 in the duodenal bulb, the site of gastric emptying, to about 7.2in the distal parts of the ileum. The pH then drops at the ileum-caceumjunction to about 6.3 and gradually increases to about 7 in thedescending (left) colon. Second, absorption of purines from the smallintestine is fast, providing for minimal degradation after release ofthe therapeutically active substance and a predictable delivery ofspecific dosage forms. Third, residence times to the point of release inthe distal part of the small intestine are predictable (3-4.5 hours).Suitable tablets of adenosine 5′-triphosphate-disodium salt wereprepared containing binders, fillers and stabilizers. The mixtures weregranulated and condensed into 250 milligrams of ATP and 500 milligramsof ATP tablets using an oval-shaped punch. The tablets had to providesmooth surfaces, free from edges or sharp curves preferably with concavesurfaces, all are properties desirable for the stability and mechanicalstrength of the enteric coating.

[0014] Stabilizers suitable for ATP disodium tablets are magnesiumstearate, silica (SiO₂)(Sylox), which are suitable stabilizers in smallwell-established amounts, sodium bicarbonate, ascorbic acid,tocopherols, and maltodextrin, which is especially effective inprotecting hygroscopic compositions such as ATP. Suitable fillers foruse with ATP in a tablet include microcrystalline cellulose,carboxymethyl cellulose, mannitol or calcium phosphate-dibasic. Bindersthat are suitable for the ATP therapeutic composition include gumarabic, gelatin, polyvinylpyrrolidone (PVP), hydroxypropylcellulose(HPC) or methylcellulose. A preparation of ATP together with selectedstabilizers, fillers and/or binders are then compressed into tablets ofoptimal size and shape to provide good mechanical strength and surfacesuitable for enteric coating. Instead of tablets, the blendedpreparations may be used to form capsules, microtablets or micropelletsall of which may, or may not be enteric coated depending on the state ofthe art.

[0015] The function of the pH-dependent enteric coating is to preventrelease of the therapeutically active pro-drug-ATP, until it reaches thetargeted or desired location of the small intestine such as the distalportion of the small intestine, the section of the ileum where the pHrises to 7.2. The coating thickness is dependent upon the size and shapeof the tablets and ranges from 20 to 80 .mu.m. Whereas the traditionalenteric polymer coating materials were designed to protect thepharmaceutically active preparation in transit through the stomach,newer coating materials allow for the pH-dependent pills to dissolveonly at higher pH's, with a great degree of accuracy. The older entericpolymer coating materials include cellulose acetate phthalate,polyvinylacetate phthalate, cellulose acetate trimelliate, polyvinylacetate phthalate and hydroxypropyl methylcellulose phthalate. Thepreferred materials for enteric coating of ATP therapeutic compositionsare methacrylic acid/methyl methacrylate copolymers, which arecommercially available from Rhom Pharma under the name Eudragit S andEudragit L. Eudragit S is a poly(metacrylic acid, methylmetacrylate) 1:2and Eudragit L is a poly(metacrylic acid, methylmetacrylate) 1:1. Bothare anionic copolymers where the ratios refer to the ratios of freecarboxyl groups to methyl ester groups. Both copolymers have a meanmolecular weight of 135,000. These two copolymers can be mixed in avariety of ratios to achieve a mechanically stable coating of pHsensitivity of between pH's 6 and 7, with Eudragit S being the preferredingredient.

[0016] After the release of the therapeutic composition of ATP in thesmall intestine, absorption of adenosine and inorganic phosphate-thecatabolic products of ATP, or of ATP itself then follows. Absorption ofATP itself is followed by a rapid degradation to adenosine and inorganicphosphate inside the vascular bed (Slakey et al. 1990; Rapaport andFontaine 1989; Rapaport and Fontaine 1989b). Both the adenosine andinorganic phosphate are then incorporated into the liver ATP pools(steady state levels), effectively expanding these pools (Rapaport andZamecnik 1976; Rapaport and Fontaine 1989). The turnover of the expandedliver ATP pools, ATP pools which supply the adenosine precursor for redblood cell ATP synthesis, then lead to the expansion of red blood cellATP pools. Expanded red blood cell ATP pools are in turn released fromred blood cells into the blood plasma compartment (extracellular) via anon-hemolytic mechanism, where they are rapidly degraded to adenosineand inorganic phosphate (Slakey et al. 1990; Rapaport and Fontaine 1989;Rapaport 1990). The overall established mechanism thus provides for theslow, continuous release of adenosine in the blood plasma after therelease of ATP at a preferred position along the distal part of thesmall intestine.

EXAMPLE 1

[0017] Therapeutic compositions consisting of 250 milligrams and 500milligrams ATP tablets were formulated. Formulation Material 250 mg ATPTablet 500 mg ATP Tablet Adenosine 5′-triphosphate 250 mg 500 mg(Disodium salt) Microcrystalline Cellulose 200 mg 200 mg Maltodestrin200 mg 100 mg Magnesium Stearate  10 mg  20 mg Sylox Silica (SiO₂)  10mg  20 mg Total 670 mg 825 mg

[0018] ATP tablets formulation materials were compressed into tabletsutilizing an oval punch. The tablets were without prominent edges andexhibited smooth concave surfaces. The tablets exhibited excellentmechanical strength and proved to be suitable for enteric coating. Sixvolunteer subjects ingested 1000 mg per day of the 250 mg or 500 mg ATPtablets, for a period of one month. No noticeable side effects werereported.

EXAMPLE 2

[0019] Each of the ATP-formulation tablets was coated with fourdifferent types of coating. The primary considerations in selectingthese coating materials were that they should be of sufficientmechanical strength, provide good protection in acidic media and releasethe therapeutic composition of ATP at pH 6.8 or higher. The followingenteric formulations were used:

[0020] 1. Eudragit FS30D, which is an acqueous version of Eudragit S,coated to 8% coating.

[0021] 2. Eudragit S100, coated from acetone/methanol to a 6% coating.

[0022] 3. Eudragit S100, coated from acetone/methanol to a 8% coating.

[0023] All of the above coatings release ATP at a pH of 7.0-7.2.

[0024] 4. A mixture of Eudragit L100 (dissolves at pH 5.5) and EudragitS100 (at a 20:80 ratio) coated from acetone/methanol to a 8% coating.Enteric coating number 4 released ATP at a pH of 6.7-6.8.

[0025] All four enteric coating formulations were stable and completelyresisted simulated gastric fluid (no enzymes) test for over 2 hours.

[0026] Six human volunteers ingested a total of 1000 milligrams of eachof the four types of enteric coated ATP pills per day (two 500 mg pillsper day, one in the morning and one in the evening) for a period of twoweeks per type of enteric coating. No side effects or discomfort of anytype were reported. The ATP pills were completely safe over the shortterm.

EXAMPLE 3

[0027] Two overweight human volunteers ingested 1000 mg per day ofenteric coated ATP pills of enteric coating type 4 of Example 2. Thesubjects were not coffee drinkers or consumers of any other form ofcaffeine. After three weeks, one subject lost 4 pounds and the othersubject lost 6 pounds without altering any other behavioral parametersuch as diet or exercise.

EXAMPLE 4

[0028] Two overweight human volunteers who are coffee drinkers,consuming an average of two cups of coffee per day, or 110-150milligrams of caffeine, ingested 1000 mg per day of enteric coated ATPpills of enteric coating type 4 of Example 2. After three weeks onesubject lost 5 pounds and the other subject lost 6 pounds withoutaltering any other behavioral parameter such as diet or exercise.

[0029] The data discussed above lead to the following conclusions:

[0030] A safe, stable, ingestable therapeutic composition of adenosine5′-triphosphate disodium (ATP) in a form of a tablet containing morethan 100 milligrams of ATP can be prepared using binders, fillers andstabilizers well-known to the skilled artisan.

[0031] A safe, stable ingestable therapeutic composition of ATP in aform of an enteric coated pill designed to dissolve in the distal partof the small intestine, can be prepared containing more than 100milligrams of ATP per pill. The distal portion of the small intestine,the ileum, contains the lowest levels of catabolic enzymes catalyzingthe degradation of ATP and adenosine.

[0032] A method for the chronic continuous administration of adenosine,which is the major catabolic product of its pro-drug ATP, has beenunexpectedly produced utilizing the oral therapeutic compositionsoutlined in 1 and 2 above. Contrary to methods of the present invention,administration of adenosine or any of its pro-drugs by injection orinfusion results in the acutely elevated levels of adenosine.

[0033] A method for the desensitization of adenosine receptors in ahuman by exposing adenosine receptors to chronically elevated levels oftheir natural agonist, adenosine.

[0034] A method for achieving weight loss in an overweight or obesehuman by desensitization of adipose tissue A₁ adenosine receptors. Theinteraction of endogenous adenosine with the A₁ adenosine receptors ofadipose tissue is known to the skilled artisan to inhibit lipolysis orthe degradation of fat. The unexpected finding is of a method forexposing these receptors to chronically elevated levels of adenosine,which desensitize these receptors towards the action of adenosine,endogenous or exogenous, resulting in the stimulation of lipolysis inhumans. The reason being that once the receptors are desensitized, theirdensity (numbers) as well as their activities are significantlydiminished, abolishing the effects of adenosine in the inhibition oflipolysis.

[0035] A method for achieving weight loss in an overweight or obesehuman by utilizing methods described above coupled with the consumptionof average levels of caffeine. Caffeine is a known antagonist ofadenosine for the A, adenosine receptors of adipose tissue. Exposure ofthe desensitized receptors to caffeine during or after the chronicadministration of adenosine, results in further stimulation of lipolysisand weight loss in humans. Once the adipose tissue A₁ adenosinereceptors are desensitized towards adenosine, their sensitivity towardscaffeine, an adenosine antagonist, is increased yielding additionalinhibition of the activities of endogenous or exogenous adenosine atthese receptors.

References Cited

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[0040] Jacobson K. A. and van Rhee A. M.: Development of selectivepurinoceptor agonists and antagonists. in Purinergic Approaches inExperimental Therapeutics, Jacobson K. A. and Jarvis M. F., Editors,Wiley-Liss, 1997, pp 101-128.

[0041] Kollias-Baker C. et al.: Myocardial adenosine receptors. inAdenosine and Adenine Nucleotides: from Molecular Biology to IntegrativePhysiology, Belardinelli L. and Pelleg A., Editors, Kluwer Publishers,1995, pp 221-229.

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What is claimed is:
 1. A method for obtaining weight loss in humans byadministering to a human suffering from overweight, an antagonist ofadenosine A₁ receptor and at least one member selected from the groupconsisting of adenosine 5′-triphosphate and adenosine 5′-monophosphate.2. A method for maintaining weight reduction in humans by administeringto a human in need of, an antagonist of adenosine A₁ receptor and atleast one member selected from the group consisting of adenosine5′-triphosphate and adenosine 5′-monphosphate.
 3. A method forpreventing weight gain in humans by administering to a human in need of,an antagonist of adenosine A₁ receptor and at least one member from agroup consisting of adenosine 5′-triphosphate and adenosine5′-monophosphate.
 4. The method according to anyone of claims 1-3wherein the amount of adenosine 5′-triphosphate or adenosine5′-monophospate is about 0.1-100 milligrams/kg of body weight per 24hours said administering is oral or sublingual.
 5. The method accordingto anyone of claims 1-3 wherein the amount of adenosine 5′-triphosphateor adenosine 5′-monophosphate is about 0.1-100 milligrams/kg of bodyweight per 24 hours and administering is topical.
 6. The methodaccording to anyone of claims 1-3 wherein the amount of adenosine5′-triphosphate or adenosine 5′-monophosphate is about 0.01-10milligrams/kg of body weight per 24 hours and administering is byinjection.
 7. The method according to anyone of claims 1-3 wherein theamount of the antagonist of adenosine A1 receptor is about 0.1-100milligrams/kg of body weight per 24 hours and administering is oral orsublingual.
 8. The method according to anyone of claims 1-3 wherein theamount of the antagonist of the adenosine A1 receptor is about 0.1-100milligrams/kg of body weight per 24 hours and administering is topical.9. The method according to anyone of claims 1-3 wherein the amount ofthe antagonist of the adenosine A1 receptor is about 0.01-10milligrams/kg of body weight per 24 hours and administering is byinjection.
 10. The method according to anyone of claims 1-3 wherein theantagonist of the adenosine A1 receptor comprises caffeine.
 11. Themethod according to anyone of claims 1-3 wherein the antagonist of theadenosine A1 receptor comprises theophylline.